Project Summary Humans and other mammals use the temporal fine structure in sounds to identify and help localize auditory objects in three-dimensional space. The broad goal of this research is both to understand how sound localization cues are processed in the brain as well as to understand how neurons in the underlying circuitry acquire the appropriate biophysical properties during development. This proposal focuses on the medial superior olive (MSO), the first and critical stage for processing interaural time differences (ITDs) from the two ears, cues that are used for horizontal sound localization as well as for understanding speech patterns in noisy environments. ITDs are computed in the MSO via the process of coincidence detection, in which the simultaneous arrival of excitatory inputs from the two ears is detected and conveyed through action potential firing with a time resolution of a few tens of microseconds. The neurons of the MSO have historically been assumed to be functionally and morphologically homogeneous. However, our preliminary data refutes this simplistic view of the MSO: we hypothesize instead that variation in dendritic morphology and electrical properties critically shapes the location of spatial receptive fields, and that these differences are in part influenced after hearing onset by the level and pattern of neural activity. We will address these questions by combining paired dendritic and somatic patch recordings, compartmental modeling, patterned LED illumination of light-sensitive channel blockers, and hearing manipulations. Aim 1 will address the functional significance of the newly discovered tonotopic diversity in electophysiological properties of MSO neurons both in vitro using patch- clamp recordings. Aim 2 will extend these analyses to understand how the functional diversity in MSO neurons is conferred by differences in the expression levels and properties of voltage-gated channels in the axon initial segment. Aim 3 will explore how the diversity of dendritic structure itself shapes the temporal requirements for optimal detection of binaural coincidence. The information from these experiments will increase our understanding of the mechanisms underlying spatial hearing in mammals, as well as the developmental processes that control the formation of a critical circuit component in the MSO. As binaural hearing is important for speech perception and language acquisition in children, a mechanistic understanding of binaural circuit function and development may ultimately inform clinical strategies for addressing hearing impairments.